From Mutation to Symptoms: A Multi-Center Study on HNF1B-Related Nephropathy in Chinese Children

From Mutation to Symptoms: A Multi-Center Study on HNF1B-Related Nephropathy in Chinese Children | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article From Mutation to Symptoms: A Multi-Center Study on HNF1B-Related Nephropathy in Chinese Children Hongying Zhang, Chunyan Wang, Xiaoyun Jiang, Xiaojie Gao, Xiaoshan Tang, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7138364/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 23 Dec, 2025 Read the published version in BMC Nephrology → Version 1 posted 18 You are reading this latest preprint version Abstract Background Hepatocyte nuclear factor 1β ( HNF1B ) pathogenic variants constitute a major genetic contributor to congenital anomalies of the kidney and urinary tract (CAKUT), with patients simultaneously exhibiting distinct extrarenal features. Among these clinical manifestations, renal disease progression is crucial for long-term outcomes, needing comprehensive evaluation. Methods Using the Chinese Children Genetic Kidney Disease Database (2017–2024), we analyzed 26 pediatric HNF1B cases to characterize renal phenotypes and genotype correlations. Results All patients exhibited abnormal renal phenotypes at diagnosis: renal cysts (50%) and multicystic dysplastic kidney (MCDK) (37.5%). Genetic analysis revealed 16 patients (61.5%) had a 17q12 deletion including HNF1B gene, while the remaining carried HNF1B intragenic mutations, including a novel c.1390-1405dup. Comparing phenotypic trajectories, 17q12 deletion cases showed earlier renal phenotype onset (median age : 0 vs 1 year 11 months, p = 0.121), while HNF1B variants showed faster renal function deterioration (latest eGFR: 85 vs 45.6 mL/min/1.73m², p = 0.11). Three of five CKD 5 children underwent kidney transplantation before 15; one developed reversible tacrolimus-induced hyperglycemia. Conclusion These results demonstrated genotype-phenotype divergence: 17q12 deletion may promote developmental renal anomalies via haploinsufficiency, while HNF1B variants likely accelerate tubular dysfunction through dominant-negative transcriptional dysregulation. Prenatal counseling, genotype-specific monitoring, and renal monitoring for affected families are recommended. HNF1B 17q12 deletion CAKUT chronic kidney disease children Figures Figure 1 Figure 2 1. Introduction The clinical validation and molecular profiling of renal cysts during prenatal or pediatric evaluations represent important elements in the differential diagnostic framework for CAKUT, which accounts for 20–30% of prenatal congenital malformations and affects approximately 3–6 in 1000 live births [ 1 ] . Among monogenic CAKUT etiologies, HNF1B mutations constitute a predominant genetic cause, with this locus demonstrating particular susceptibility to pathogenic de novo variants [ 2 ] . As a pivotal transcription factor governing embryonic organogenesis, particularly in the kidney and pancreas, HNF1B mutation is initially found to be responsible for Renal Cysts and Diabetes syndrome (RCAD; OMIM #137920) or Maturity-Onset Diabetes of the Young 5 (MODY5; OMIM #604284), following an autosomal dominant inheritance pattern [ 3 , 4 ] . Of clinical significance, since glucose homeostasis abnormalities in HNF1B syndrome remain pharmacologically modifiable, kidney failure has emerged as the predominant prognostic determinant [ 5 , 6 ] . Therefore, systematic characterization of HNF1B genotype-phenotype relationships, particularly focusing on renal manifestations, is crucial for both mechanistic understanding and clinical management. As a member of the homeodomain-containing transcription factor superfamily, HNF1B comprises an amino-terminal dimerization domain, a bipartite POU-type DNA-binding domain, and a carboxy-terminal transactivation domain interacting with key coactivators and corepressors in organogenesis and homeostasis [ 7 ] . Specifically for the kidney development, HNF1B plays critical roles in multiple morphogenetic processes, including ureteric bud branching, nephron patterning, and tubulogenesis. HNF1B absence prevents mesenchymal to epithelial transition, ultimately leading to renal hypoplasia [ 8 ] . When Hnf1b is deleted during the tubular elongation phase, a multicystic phenotype emerges, accompanied by downregulation of cystogenesis-related genes, such as Pkd2 , Pkhd1 , and Umod [ 9 , 10 ] . For postnatal kidney, HNF1B is involved in tissue maintenance and responsible for metabolism and solute transport partially through regulating the expression of FXYD2, a key regulator for renal magnesium (Mg²⁺) reabsorption [ 11 ] . Consequently, HNF1B mutations can disrupt electrolyte homeostasis, another observable clinical phenotype. Notably, not all HNF1B abnormalities are associated with electrolyte disorder. In vitro studies have shown that specific mutations modify the expression networks of downstream target genes, suggesting a potential mechanism underlying phenotypic heterogeneity [ 12 ] . Thus, exploring the correlation between HNF1B mutation types and clinical phenotypes would facilitate the establishment of a precise diagnostic system for HNF1B -related disorders. In this study, a pediatric cohort comprising 26 children with HNF1B-related disorders was established using the CCGKDD. After systematically analyzing their phenotypic and genotypic characteristics, we found that the 17q12 deletion cohort exhibited earlier onset of fetal renal phenotypic abnormalities(median age: 0 vs 1 year 11 months, p = 0.121), whereas the HNF1B mutation group displayed more severe renal functional deterioration at final follow-up (latest estimated glomerular filtration rate (eGFR) : 85 vs 45.6 mL/min/1.73m², p = 0.11). These phenotypic divergences likely stem from distinct genetic mechanisms, including transcription factor dominant-negative effects and haploinsufficiency-mediated pathways. Moreover, for HNF1B -mutated kidney transplant recipients developing tacrolimus-associated hyperglycemia, conversion to cyclosporine A or sirolimus represents an effective therapeutic strategy. 2. Participants and Methods 2.1 Subjects A total of twenty-six Chinese pediatric patients with HNF1B mutations from CCGKDD were enrolled. The inclusion criteria required: (1) molecular diagnosis of HNF1B with pathogenic variants by sequencing, and (2) comprehensive clinical documentation. Detailed phenotypic data including renal manifestations, diabetes status (in probands or family members), and other clinical features, were collected from institutional medical records. All the enrolled cases were distributed in four centers, scattered over thirteen province/municipalities (seventeen cities) in China. 2.2 Clinical diagnosis All patients enrolled in this study were primarily diagnosed by pediatric nephrologists. CAKUT, pancreatic and hepatobiliary tract malformations were defined as structural abnormalities in the imaging tests, including ultrasonography, X-ray fluoroscopy, computed tomography, or magnetic resonance imaging. Hyperuricemia in children/adolescents was defined as serum uric acid levels ≥ 5.5 mg/dL [ 13 ] . Electrolyte abnormalities were diagnosed when abnormal levels were persisted or necessitated intervention. Hypomagnesemia was defined as serum magnesium concentrations < 0.65 mmol/L. Diabetes was diagnosed as patients with chronic hyperglycemia meeting the following criteria repeatedly: (1) fasting plasma glucose level of ≥ 126 mg/dL; (2) 2-h post-load glucose ≥ 200 mg/dL during a 75 g oral glucose tolerance test; (3) random plasma glucose ≥ 200 mg/dL [ 14 ] . The estimated glomerular filtration rate (eGFR) was calculated from serum creatinine and body height according to the Schwartz formula [ 15 ] . Chronic kidney disease (CKD) stages I–V were defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group guidelines [ 16 ] . Genital abnormalities and neurological abnormalities were diagnosed by primary doctors. 2.3 Genetic analysis Genetic studies for probands and available first-degree relatives included whole exome sequencing (WES), whole genome sequencing (WGS), gene copy number variation (CNV), quantitative polymerase chain reaction (qPCR) or kidney panel examination. Peripheral venous blood (2–4 mL) was collected to extract genomic DNA using the Blood genome column medium extraction kit following the manufacturer’s instructions (Kangweishiji, China). All sequencing was performed by the Beijing Chigene Translational Medicine Research Center Co., Ltd., Beijing, China. The paired-end reads were aligned to the Ensembl GRCh37/hg19 reference genome using Burrows-Wheeler Aligner (BWA). Single nucleotide variants (SNVs) and small insertions/deletions (Indels) were called using the Genomic Analysis Toolkit (GATK) software (version 4.1.7). Copy number variant (CNV) were detected using the Exon Depth algorithm. Sequence alterations were checked against published polymorphism/mutations and evaluated for conservation across species. Pathogenicity analysis of variants was performed according to the American College of Medical Genetics and Genomics (ACMG) practice guidelines. Bidirectional Sanger sequencing was performed to validate the screened variants. Multiple computational software (Human Splicing Finder 3.1, PolyPhen-2, Mutation Taster, and VarCards) were used to evaluate the pathogenic effects of variants. 2.4 Molecular modeling and structural analysis The 3D modeled structures of HNF1B protein for the wild-type and mutant types were prepared using homology modeling in SWISS-MODEL. Structural analysis was analyzed and visualized using the PyMOL software. 2.5 Statistical analysis Continuous variables are presented as median (range). Mann-Whitney test was used for comparison of non-normal distributed continuous variables between the two groups, while Fisher exact probability test was used for categorical variables. Kaplan-Meier survival curves were employed to compare the renal survival using end-stage renal disease (ESRD) as an end point. A p value < 0.1 was considered to be statistically significant. IBM SPSS Statistics 25 software (IBM Co., Armonk, NY, USA) was used for all calculation. 3. Results 3.1 Clinicopathological analysis of renal disorders 26 HNF1B-associated pediatric patients consisted of 10 males, 14 females, and 2 cases with unrecorded sex. The median age at disease onset was birth (range: birth-5.3 years), whereas the median age at genetic diagnosis was 5.8 years (range: 1.3–7.5 years). Corresponding to median disease onset at birth, 15 cases exhibited abnormal renal findings on prenatal ultrasound. The spectrum included: hyperechoic kidneys (HE; 5/15), hydronephrosis (HN; 3/15), renal dysplasia (3/15), cysts (3/15), abnormal amniotic fluid volume (3/15), and solitary kidney (1/15). Notably, 3 cases presented with two concurrent abnormalities (primarily involving amniotic fluid volume). Transitioning to postnatal evaluation, 24 cases universally demonstrated renal abnormalities on ultrasound. And the postnatal phenotype diverged from prenatal findings, with cysts emerging as the dominant feature (12/24), followed by MCDK (9/24) and renal dysplasia (5/24; defined by loss of corticomedullary differentiation and/or increased echogenicity). Rare manifestations comprised ectopic kidney, duplex kidney, vesicoureteral reflux (VUR), and nephrocalcinosis, each observed in one case. This phenotypic evolution suggests progressive renal pathology from fetal to childhood stages in HNF1B -related nephropathy (Table 1 ). Table 1 Phenotypes and genetypes of the patients. Case Age sex Family history Prenatal renal assessment Postnatal renal phenotype Extral-renal phenotype HNF1B gene mutation (accession no: NM_000458) or 17q12 deletion (assembly: GRCh37) Mutation origin onset GD 1 0 4y F No HE (B) Cyst (B), CKD1 No 17q12 deletion; chr17: 34815551–36249430 (1.4 Mb) NA 2 0 1y1m M father: HN (R) and Cyst (B) Dysplasia (L) dysplasia (L), Cyst (R) MD 17q12 deletion; chr17: 34536497–36388301 (1.85 Mb) Paternal 3 0 5y9m M No HE (B) MCDK (B), HUA, CKD 2 DD 17q12 deletion; NA NA 4 8y5m 8y5m M mother: Cyst and stones (B) No dysplasia (B), HE (B), HUA, proteinuria, CKD 3 No c.578 T > C (exon 3), p.M193T Maternal 5 0 2y8m F No dysplasia (B), Oligohydramnios MCDK (B), HN (B), HUA, CKD4 DD 17q12 deletion; chr17: 34775520–36278036 (1.5Mb) Maternal 6 0 3m F No HN (L) Cyst (B), HN (L), CKD 1 No 17q12 deletion; chr17: 34765237–36276584 (1.52Mb) De novo 7 0 5m M No dysplasia(B) dysplasia (B), HE (B), HUA, CKD 5 No c.441G>T (exon 2), p.Q147H De novo 8 11y9m 11y10m F No No Cyst (L), MCDK (R), proteinuria, HUA, CKD 4 No c.1339 + 5 (IVS6) G > T De novo 9 1y3m 1y4m M No Oligohydramnios MCDK (L), HE (B), HUA, CKD 2 No 17q12 deletion; chr17: 34836666–36241241 (1.4Mb) De novo 10 7m 11m F No No MCDK (B), HE (B), NC (B), HUA, CKD 3 SP c.493C>G(exon 2), p.R165G De novo 11 7y9m 7y9m F No No MCDK (R), HUA, CKD 5 DD 17q12 deletion; chr17: 34495987–36293050 (1.8Mb) Maternal 12 0 1y6m F No HN MCDK (L), HUA, CKD 1 EP 17q12 deletion; chr17: 34581399–36347081 (1.77Mb) De novo 13 7y6m 7y6m M No No HN (L), dysplasia (R), VUR (B) No c.364G>T(exon 2), p.A122S Paternal 14 5y11m 5y11m F No No Cyst (B), HE (B), CKD 2 SP 17q12 deletion; chr17: 34493374–36104875 (1.61Mb) NA 15 2m 2m F No No Cyst (B), proteinuria elevated ALT/AST 17q12 deletion; chr17: 34842526–36104883 (NA) NA 16 3y6m 13y10m F No No HE (B), HUA , CKD 3 No c.662A>T(exon 3), p.D221V Paternal 17 0 6y3m M No SK (R) dysplasia (L), EK (L), CKD 2 No 17q12 deletion; chr17: 34806197–36104875 (1.3Mb) De novo 18 0 2y10m M father: Cyst (B); grandmother: CKD 5 Cyst(B) MCDK(B), HUA, CKD 2 HypoMg c.541C>T(exon 2), p.R181X Paternal 19 0 0 M No Cyst (R) MCDK(L), Cyst (R), HUA, CKD 2 No c.544 + 3_544 + 6 (IVS2) delAAGT Maternal 20 0 0 unknown mother: Cyst (B) HE (B), HN (R) NA No c.1006del(exon 4), p.H336Tfs*40 Maternal 21 0 0 unknown No HE (B), hydramnios NA No 17q12 deletion;chr17: 34434562–36252160 (1.82Mb) De novo 22 8y5m 8y5m F No No Cyst (B), CKD 5 No c.1390–1405 dup (exon 7), p.L469Rfs*87 Maternal 23 2y 15y F father: Cyst (B); grandfather: DM No Cyst (B), HUA, CKD5 DM, elevated ALT/AST 17q12 deletion; chr17: 34836666–36225059 (1.26Mb) Paternal 24 6y10m 6y10m M No No Cyst (B); HUA, CKD 5 DM 17q12 deletion; chr17: 34497248–36104875 (1.61Mb) De novo 25 0 6y9m F No Cyst Cyst (B); CKD 1 PC 17q12 deletion; chr17: 34806197–36104875 (1.3Mb) De novo 26 0 6y9m F No HE (B) Cyst (B), duplicate kidney (L); CKD 1 No 17q12 deletion; chr17: 34842543–36104875 (1.26Mb) De novo Different from the cyst-dominant pathology observed on imaging, renal functional outcomes in HNF1B-related children demonstrated marked heterogeneity. Hyperuricemia was present in 58.3% (14/24) of patients, while microalbuminuria, a marker of early glomerular injury, was detected in 12.5% (3/24). Longitudinal follow-up (median: 15 months; range: 6–31 months) revealed that nearly half of the cohort (10/21, 47.6%) progressed to advanced CKD (stages 3–5). Among the 5 patients who progressed to CKD 5, 3 underwent successful renal transplantation with stable graft function. 1 developed post-transplant hyperglycemia managed by switching immunosuppression from tacrolimus to cyclosporine A, indicating cyclosporine A may offer superior glycemic control in pediatric HNF1B associated nephropathy patients with post-transplant hyperglycemia. Meanwhile, two remained on regular peritoneal dialysis. 3.2 Extrarenal symptoms Given HNF1B 's critical role as a transcription factor in multi-organ development, extrarenal manifestations exhibit a distinct phenotypic pattern, primarily including pancreatic hypoplasia with exocrine dysfunction. Notably, while pancreatic developmental anomalies are common, the clinical onset of associated diabetes occurs significantly later than renal manifestations. This temporal discrepancy suggests either differential organ sensitivity to HNF1B deficiency or, more likely, divergent developmental timing of HNF1B expression across organs. Among our cohort, diabetes mellitus developed in 2 patients despite normal pancreatic morphology. Conversely, 3 patients maintained normal blood glucose levels with pancreatic developmental anomalies, including 2 hypoplastic pancreas and 1 multiple pancreatic cyst. Additionally, 2 showed elevated transaminases, 1 had hypomagnesemia, and 5 presented with neurological developmental abnormalities, including 1 epilepsy, 1 cerebral hypoplasia, and 3 psychomotor retardation. Notably, because of age-dependent penetrance, cryptic clinical features (e.g., asymptomatic hypomagnesemia and mildly elevated transaminases), and diagnostic limitations (e.g., routine pediatric exams lacking pancreatic/reproductive assessments), the extrarenal symptoms in our cohort may be underdiagnosed. To improve patients' quality of life and better characterize genotype-phenotype correlations, enhanced emphasis for extrarenal symptoms on further follow-up may be warranted in HNF1B -related disorders. 3.3 Genotype Genetic studies revealed total gene deletion of 17q12 in 16 patients (61.5%), 6 missense mutation (23.1%), 2 splice mutation (7.7%), 1 deletion and 1 duplicate mutation (7.7%), among which c.1390-1405dup in exon 7 was unreported (Fig. 1 a). Notably, although c.1390-1405dup caused a frameshift translation due to a non-triplet 16 base pair (bp) repeat, it did not lead to premature termination. Instead, it resulted significant changes of the last 89aa, corresponding to C-terminal transactivation domain (p.L469Rfs*87) and likely disrupting the interaction with coactivator/corepressor (Fig. 1 b). Interestingly, 3D protein structure modeling suggested that beyond the local structural disruption after amino acid 469, spatial rearrangements also occur in regions with unchanged amino acid composition, indicating that the mutation may induce allosteric effects through long-range conformational propagation and further affecting overall protein stability or function (Fig. 1 c). Moreover, the proband inherited the mutation maternally, with the mother showing no phenotypic abnormalities. In contrast, the proband exhibited rapid renal deterioration leading to CKD 5 and is currently managed with peritoneal dialysis. Cascade screening of parental DNA in 22 patients identified HNF1B mutation transmission in 11 families, without significant parent-of-origin effect bias (6/11 showing maternal and 5/11 paternal inheritance). Five parental mutation carriers exhibited clinical symptoms of renal cysts. Among these inherited mutations, the molecular subtypes were whole gene deletion (4/11), missense mutation (3/11), splice site mutation (1/11), nonsense mutation (1/11), and indel mutation (2/11). The remaining 50% harbored de novo HNF1B mutations, highlighting the significant contribution of spontaneous genetic alterations in this cohort. Among these, 8/11 constituted complete gene deletions (17q12 deletion), 2/11 missense, and 1/11 spice mutation. Overall, 17q12-related HNF1B whole gene deletions were the predominant type in our HNF1B mutation spectrum, with no significant difference in the proportion of inherited versus de novo mutations. Additionally, our study also confirmed that HNF1B mutations remained highly clustered in the known hotspots of exon 2 and exon 3. 3.4 Genotype-Phenotype Correlations Based on the reported mutated genotype dichotomy of HNF1B , the study cohort was stratified into two groups based on genetic testing results: the 17q12 deletion group (16/26) and the HNF1B mutation group (10/26). Our findings demonstrated a higher prevalence of prenatal renal phenotypic abnormalities in the 17q12 deletion group compared to the HNF1B group ( p = 0.300), suggesting an earlier onset of renal manifestations in the former. During the follow-up period (median follow-up duration: 27.9 months in 16 pediatric patients), the 17q12 deletion group exhibited a faster eGFR decline per unit time compared to the HNF1B group (0.71 [-0.51, 3.83] vs. 0 [-0.95, 4.24] mL/min/1.73m²/year, p = 0.227). The kidney survival rates at the 4-year and 12.5-year follow-up were 80% and 25%, respectively (Fig. 2 a). However, at the latest follow-up assessment, the median eGFR in the 17q12 deletion group was significantly higher than that in the HNF1B group (85 [10–135] vs. 45.66 [10-87.7] mL/min/1.73m 2 , p = 0.110) (Fig. 2 b). At the latest follow-up, a greater proportion of patients in the HNF1B group had progressed to CKD stages 3–5 than those in the 17q12 deletion group ( p = 0.08), indicating more severe postnatal renal dysfunction in HNF1B variant carriers. All five cases with neurological abnormalities occurred in the 17q12 deletion group, while no neurodevelopmental disorders were observed in the HNF1B group ( p = 0.116). This phenotypic distinction may reflect additional neurodevelopmental genes within the 17q12 deletion region, although statistical significance was not reached. No statistically significant differences were observed between the two genotypes in the distribution of secondary manifestations including hyperuricemia, hypomagnesemia, diabetes mellitus, pancreatic abnormalities, hepatic dysfunction, or genitourinary malformations(Table 2 ). Table 2 Comparison of clinial phenotypes between patients with 17q12 deletions and HNF1B variants Characteristics 17q12 deletion (16) HNF1B variant (10) p value Age (months) at onset 0 (0–93) 23 (0-141) 0.121 Age (months) at GD 69 (2-180) 90 (5-166) 0.325 Prenatal ultrasound abnormalities 11/16 4/10 0.300 Latest eGFR 85 (10–135) 45.6 (10-87.7) 0.110 eGFR decline rate (mL/min/1.73m²/year) 0.71 (-0.51, 3.83) 0 (-0.95, 4.24) 0.277 Latest CKD Stage 0.080 CKD stage 1–2 9/13 2/8 CKD stage 3–5 4/13 6/8 Hyperuricemia 6/15 4/9 1.000 Hypomagnesemia 0/14 1/8 0.364 Diabetes mellitus 2/11 0/9 0.479 Pancreatic abnormolities 2/11 1/7 1.00 Liver abnormalities 2/14 0/8 0.515 Genital abnormalities 0/6 0/5 NC Neurological abnormality 5/14 0/9 0.116 4. Discussion Based on the transcription factor characteristics of the HNF1B , several cohorts have adopted a mutated genotype dichotomy (distinguishing between intragenic HNF1B mutations and 17q12 deletion spanning 15 genes including HNF1B ) to investigate genotype-phenotype correlations. While convergent themes exist across studies, discrepancies in certain aspects also emerge, potentially reflecting variations in cohort characteristics and analytical approaches. Ulinski et al. found no difference in renal function or severity of renal morphologic lesions between patients with HNF1B deletions and point mutations [ 17 ] . And Okorn et al. identified a maternal transmission bias and reported that renal cyst progression was correlated positively with declining renal function, early-onset ESRD (before 2 years of age) was associated with bilateral dysplasia. Notably, both outcomes occurred independently of the mutant genotype [ 18 ] . In this study, we found that the 17q12 deletion group exhibited a higher prevalence of fetal renal abnormalities compared to HNF1B mutation group, suggesting earlier onset of kidney manifestations in deletion carriers. A cohort study focusing on 17q12 deletions reported a 65% prevalence of prenatal renal ultrasound abnormalities, which was close to the 68% in our study [ 19 ] . Mechanistically, the 17q12 deletion results in HNF1B haploinsufficiency, probably reducing its expression below the critical threshold required for normal nephrogenesis, a phenomenon consistent with the exquisite dosage sensitivity of transcription factors during embryonic cell fate determination [ 20 ] . In contrast, HNF1B missense/truncating mutations may retain partial protein activity, which could sustain early renal development through the compensation by other proteins, such as HNF1A. Moreover, a recent study utilizing human induced pluripotent stem cells (hiPSCs) demonstrated that precisely timed attenuation of Wnt/β-catenin signaling was required to achieve optimal HNF1B activation, which was necessary for proper mesenchymal-epithelial transition (MET) during kidney tubule formation, highlighting the importance of HNF1B expression levels [ 8 ] . On the other hand, our longitudinal follow-up revealed that patients in the HNF1B mutation group progressed to advanced CKD stages (3–5) more frequently than those with 17q12 deletions, suggesting accelerated postnatal renal functional decline in mutation carriers, consistent with conclusion in that compared with the patients with mutations, those with HNF1B deletion less had CKD 3–4/ESRD at diagnosis and in the long term [ 21 ] . This phenotypic divergence may stem from dominant-negative effects exerted by mutant HNF1B proteins, with distinct molecular consequences based on mutation localization. Specifically, when mutations occur within the DNA-Binding domain, the mutant protein retains dimerization capacity but impairs DNA recognition. For transactivation domain (TAD) -localized variants, mutant proteins maintain DNA binding capability but fail to recruit coactivators or coinhibitor due to disrupted interaction interfaces. In either case, these mutant proteins with compromised functions competitively occupy regulatory elements, progressively impairing wild-type protein function through a dominant-negative effect. Notably, the inhibitory effect may exhibit gradually intensified characteristics as the mutant protein proportion accumulates over time. In our cohort, no specific mutational loci within the HNF1B gene demonstrated preferential association with the progression to advanced kidney disease. Notably, patient 22 harbored a novel HNF1B mutation (c.1390-1405dup, p.L469Rfs*87) in exon 7, different from the hotspot mutation (exon 2 and exon 3) and representing the first reported duplication affecting the C-terminal TAD. Clinically, the patient exhibited rapidly progressive renal phenotype, eventually developing CKD 5, requiring regular peritoneal dialysis and awaiting renal transplantation. The mutation was maternally inherited, but the mother remained asymptomatic, possibly due to incomplete penetrance, consistent with previous observation that the phenotype can vary considerably among persons carrying the same HNF1B mutation, even among members of the same family [ 22 ] . Thus, prenatal screening for females from HNF1B -mutated families should integrate “genetic testing plus imaging assessment plus genetic counseling” to confirm mutation carriage, rather than absolutely predict phenotypes. Clinically, it is essential to emphasize to parents the uncertainty of penetrance and advocate for long-term postnatal monitoring combined with environmental interventions (e.g., weight control, low-sugar diet) to mitigate the risk of phenotypic expression. Although this study primarily focused on renal phenotypes associated with HNF1B mutations, it was important to recognize that HNF1B also serves as a critical transcriptional regulator of pancreatic development and function, whose mutation could develop early-onset diabetes. Given that a subset of pediatric HNF1B patients progress to CKD 5, renal transplantation remains the preferred renal replacement therapy. Thus, the impact of immunosuppressant selection on post-transplantation glycemic control requires heighted attention. In this study, three post-transplant children initially received tacrolimus for rejection prophylaxis, but one developed hyperglycemia, which resolved after switching from tacrolimus to cyclosporine A (CsA), both of which are cornerstone agents in post-transplant immunosuppression, although tacrolimus is often favored in pediatric renal transplantation due to its superior efficacy and a more favorable side-effect profile. Mechanistically, Tacrolimus impairs glucose metabolism by inhibiting the calcineurin-NFAT pathway, which disrupts β-cell insulin secretion, activates mTOR signaling, leads to peripheral insulin resistance and reduces glucose uptake [ 23 ] . A Meta-analysis showed that tacrolimus use was associated with a higher incidence of new-onset diabetes than CsA after transplantation (NODAT) [ 24 ] . Therefore, based on these findings, the dual risk of HNF1B -related diabetes and CNI-induced hyperglycemia necessitates a proactive, individualized immunosuppressive strategy in transplant recipients. In conclusion, this study demonstrates that the 17q12 deletion group exhibited earlier fetal renal phenotypes, while the HNF1B mutation group showed worse renal function at follow-up end, which was probably linked to genetic mechanisms including transcription factor haploinsufficiency and dominant-negative effects. For HNF1B -mutated patients post-kidney transplantation, if hyperglycemia develops during tacrolimus therapy, substitution with cyclosporine A or mTOR inhibitors (e.g., sirolimus) is preferred. The primary limitation of this study is the small sample size, coupled with incomplete assessment of extrarenal phenotypes in certain cases, which may have introduced bias in phenotype analysis. Future studies with larger sample sizes, comprehensive phenotypic profiling, and extended follow-up durations are essential to fully characterize the clinical landscape of HNF1B -related disorders. Such investigations will facilitate the development of evidence-based prognostic interventions, thereby enhancing our ability to inform clinical management and improve outcomes for affected individuals. Abbreviations CAKUT: congenital anomalies of the kidney and urinary tract; CCGKDD: Chinese Children Genetic Kidney Disease Database; MCDK: multicystic dysplastic kidney; eGFR: estimated glomerular filtration rate; CKD: Chronic kidney disease; ESRD: end-stage renal disease; TAD: transactivation domain; CsA: cyclosporine A; GD: genetic diagnosis; y: year, m: month. B: bilateral. L: left. R: right. HN: hydronephrosis. Cyst: multiple renal cysts. CKD: chronic kidney diease. DM: diabetes mellitus. MCDK: multicystic dysplastic kidney. HUA: hyperuricaemia. HE: renal parenchymal hyperechogenicity. NC: nephrocalcinosis. VUR: vesicoureteral reflux. SK: solitary kidney. EK: ectopic kidney. ALT: alanine transaminase. AST: aspartate transaminase. PC: pancreatic cyst. NA: not available. DD: developmental delay. MD: myelination dysplasia. EP: epilepsy. SP: small pancreas. Declarations Ethics approval and consent to participate All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the [Ethics Committee of Wuhan Children’s Hospital] (Approval number: [2024R141-E01]). Consent for publication Written informed consent was obtained from all participants. In accordance with federal and institutional guidelines, informed consent was obtained from the legal guardians for pediatric patients younger than the age of 16, while informed consent was obtained directly from pediatric patients aged over 16 years themselves. Availability of data and materials The data that support the finding of this study are available from the corresponding author upon reasonable request. The ClinVar accession number for the present HNF1B variants are VCV004071464.1, VCV000635616.9, VCV000635666.10, VCV000635668.11, VCV000372381.24, VCV004071465.1, VCV004071463.1, VCV004071466.1, and VCV000805639.10. Competing Interests The authors declare no conflict of interest. Funding This work was supported by Construction Project of Research Division of Children's Kidney Disease of Wuhan Children's Hospital (2022FEYJS003), Knowledge and Innovation Project of Wuhan Science and Technology Bureau (2023020201010197), Hubei Provincial Health Commission Joint Fund Project (WJ2023M149), and Shanghai “Rising Stars of Medical Talents” Youth Development Program (SHWSRS(2023)_070). Authors' contributions All authors contributed to the intellectual content of this manuscript and approved the final manuscript as submitted. HZ collected data and drafted the manuscript with the help of CW, XJ and XG, HY and PL and LH performed gene analysis and generated figures, XT, JL, RD and AZ interpreted the data, QS, XW and HX revised the article for important intellectual content. All authors have critically read and approved the manuscript. Acknowledgments We thank all patients and their families for their participation in this study. References Kolvenbach, C.M., S. Shril, and F. Hildebrandt, The genetics and pathogenesis of CAKUT. Nature Reviews Nephrology, 2023. 19(11): p. 709-720. Sawaf, H., et al., Genetic Susceptibility to Chronic Kidney Disease: Links, Risks and Management. Int J Nephrol Renovasc Dis, 2023. 16(11): p. 1-15. Kolatsi-Joannou, M., et al., Hepatocyte nuclear factor-1beta: a new kindred with renal cysts and diabetes and gene expression in normal human development. J Am Soc Nephrol, 2001. 12(10): p. 2175-2180. Bellanné-Chantelot, C., et al., Large genomic rearrangements in the hepatocyte nuclear factor-1beta (TCF2) gene are the most frequent cause of maturity-onset diabetes of the young type 5. Diabetes, 2005. 54(11): p. 3126-32. Buffin-Meyer, B., et al., Renal and Extrarenal Phenotypes in Patients With HNF1B Variants and Chromosome 17q12 Microdeletions. Kidney Int Rep, 2024. 9(8): p. 2514-2526. Faguer, S., et al., Calcineurin Inhibitors Downregulate HNF-1β and May Affect the Outcome of HNF1B Patients After Renal Transplantation. Transplantation, 2016. 100(9): p. 1970-8. Barbacci, E., et al., HNF1beta/TCF2 mutations impair transactivation potential through altered co-regulator recruitment. Hum Mol Genet, 2004. 13(24): p. 3139-49. Ng-Blichfeldt, J.P., et al., Identification of a core transcriptional program driving the human renal mesenchymal-to-epithelial transition. Dev Cell, 2024. 59(5): p. 595-612.e8. Bohn, S., et al., Distinct molecular and morphogenetic properties of mutations in the human HNF1beta gene that lead to defective kidney development. J Am Soc Nephrol, 2003. 14(8): p. 2033-41. Gresh, L., et al., A transcriptional network in polycystic kidney disease. Embo j, 2004. 23(7): p. 1657-68. Adalat, S., et al., HNF1B mutations associate with hypomagnesemia and renal magnesium wasting. J Am Soc Nephrol, 2009. 20(5): p. 1123-31. Grand, K., et al., HNF1B Alters an Evolutionarily Conserved Nephrogenic Program of Target Genes. J Am Soc Nephrol, 2023. 34(3): p. 412-432. Gois, P.H.F. and E.R.M. Souza, Pharmacotherapy for hyperuricemia in hypertensive patients. Cochrane Database Syst Rev, 2017. 4(4): p. Cd008652. Seino, Y., et al., Report of the committee on the classification and diagnostic criteria of diabetes mellitus. J Diabetes Investig, 2010. 1(5): p. 212-28. Schwartz, G.J., L.P. Brion, and A. Spitzer, The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin North Am, 1987. 34(3): p. 571-90. Stevens, P.E. and A. Levin, Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. Ann Intern Med, 2013. 158(11): p. 825-30. Ulinski, T., et al., Renal phenotypes related to hepatocyte nuclear factor-1beta (TCF2) mutations in a pediatric cohort. J Am Soc Nephrol, 2006. 17(2): p. 497-503. Okorn, C., et al., HNF1B nephropathy has a slow-progressive phenotype in childhood-with the exception of very early onset cases: results of the German Multicenter HNF1B Childhood Registry. Pediatr Nephrol, 2019. 34(6): p. 1065-1075. Verscaj, C.P., et al., Characterization of the prenatal renal phenotype associated with 17q12, HNF1B, microdeletions. Prenat Diagn, 2024. 44(2): p. 237-246. Rice, A.M. and A. McLysaght, Dosage sensitivity is a major determinant of human copy number variant pathogenicity. Nat Commun, 2017. 8: p. 14366. Dubois-Laforgue, D., et al., Diabetes, Associated Clinical Spectrum, Long-term Prognosis, and Genotype/Phenotype Correlations in 201 Adult Patients With Hepatocyte Nuclear Factor 1B (HNF1B) Molecular Defects. Diabetes Care, 2017. 40(11): p. 1436-1443. Madariaga, L., et al., Variable phenotype in HNF1B mutations: extrarenal manifestations distinguish affected individuals from the population with congenital anomalies of the kidney and urinary tract. Clin Kidney J, 2019. 12(3): p. 373-379. Rodriguez-Rodriguez, A.E., et al., Inhibition of the mTOR pathway: A new mechanism of β cell toxicity induced by tacrolimus. Am J Transplant, 2019. 19(12): p. 3240-3249. Oliveras, L., et al., Immunosuppressive drug combinations after kidney transplantation and post-transplant diabetes: A systematic review and meta-analysis. Transplant Rev (Orlando), 2024. 38(3): p. 100856. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 23 Dec, 2025 Read the published version in BMC Nephrology → Version 1 posted Editorial decision: Revision requested 01 Sep, 2025 Reviews received at journal 28 Aug, 2025 Reviews received at journal 25 Aug, 2025 Reviews received at journal 22 Aug, 2025 Reviews received at journal 21 Aug, 2025 Reviews received at journal 20 Aug, 2025 Reviewers agreed at journal 13 Aug, 2025 Reviewers agreed at journal 13 Aug, 2025 Reviewers agreed at journal 13 Aug, 2025 Reviewers agreed at journal 12 Aug, 2025 Reviewers agreed at journal 12 Aug, 2025 Reviewers agreed at journal 11 Aug, 2025 Reviewers agreed at journal 11 Aug, 2025 Reviewers invited by journal 08 Aug, 2025 Editor assigned by journal 08 Aug, 2025 Editor invited by journal 31 Jul, 2025 Submission checks completed at journal 31 Jul, 2025 First submitted to journal 31 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7138364","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":500148132,"identity":"975c3fae-923a-401e-8a4f-3be333ed9225","order_by":0,"name":"Hongying Zhang","email":"","orcid":"","institution":"Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital, Huazhong University of Science \u0026 Technology","correspondingAuthor":false,"prefix":"","firstName":"Hongying","middleName":"","lastName":"Zhang","suffix":""},{"id":500148133,"identity":"e07862a7-cbdf-44c8-9530-255a13e0ff0f","order_by":1,"name":"Chunyan 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Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/ElEQVRIiWNgGAWjYDACZiTmww8GNjz8/A3Ea2EzlihIk5GccYAEGyV4Phy2MWhIwK/K4Djzw8c8FXcS+2e3XzCQMDjPY8BwgPHDxxzcWiSb2YyNec48S5xx50zBgwKD2zzmzA3MkjO34dbCz8xgJp3bdji34UZOAtCW2zyWDQfYmHnxaGFjZv8mnfvvcO58oBYJHoNzPAYHEvBr4WfmAdrScDh3w430A0AtBwhrkWzmKTb+c+xw/cYbOcBANkjmkZxxsBmvXwzOH9/4cEbNYWO5G+mPH374Y2fPz9988MNHPFqQADB4IYCxgSj1QMD+gFiVo2AUjIJRMMIAAKOQU+cSsWt+AAAAAElFTkSuQmCC","orcid":"","institution":"Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital, Huazhong University of Science \u0026 Technology","correspondingAuthor":true,"prefix":"","firstName":"Xiaowen","middleName":"","lastName":"Wang","suffix":""},{"id":500148156,"identity":"642062cf-e7ad-490a-8328-7213a0eddf79","order_by":14,"name":"Hong Xu","email":"","orcid":"","institution":"Children’s Hospital of Fudan University, National Children’s Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Hong","middleName":"","lastName":"Xu","suffix":""}],"badges":[],"createdAt":"2025-07-16 09:38:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7138364/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7138364/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12882-025-04616-z","type":"published","date":"2025-12-23T15:57:32+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":89232506,"identity":"b1af510b-13f9-4f91-9470-8939b5997805","added_by":"auto","created_at":"2025-08-17 14:25:24","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":502604,"visible":true,"origin":"","legend":"\u003cp\u003eGenetic characterization of patients with HNF1B mutations. (a) Schematic illustration of mutation sites in HNF1B gene. Distinct terminal symbols of the lines represent various mutation types. Distinct colors of the lines denote the CKD stage at last follow-up, while the gray dashed lines indicate that the CKD stage was unobtainable. (b) Deduced amino acid sequences were shown for wildtype (top) and unreported c.1390-1405dup (bottom) sequences. (c) Predicted 3D structural changes of HNF1B protein caused by C-terminal 89-amino acid frameshift translation (c.1390-1405dup；p.L469Rfs*87). Red arrows indicate 3D conformational changes; black text: wild-type amino acid residues with altered spatial configuration; red text: novel residues resulting from frameshift translation. The aa469 where frameshift translation initiates is zoomed and shown in the right panel.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7138364/v1/861a272c0268b499be369a25.jpeg"},{"id":89231067,"identity":"afe6a21b-ca70-480f-b474-0d3877726dd1","added_by":"auto","created_at":"2025-08-17 14:17:24","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":138314,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier cumulative kidney survival rates in all patients (a) and according to the genotype (b).\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7138364/v1/f4c85c028f0be9767d1196f2.jpeg"},{"id":99172288,"identity":"e3d4f7d0-6555-406e-86d4-ba2b7efb61c7","added_by":"auto","created_at":"2025-12-29 16:07:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1775035,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7138364/v1/a3db3d0e-d63c-42e7-b829-d0ba95243e65.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"From Mutation to Symptoms: A Multi-Center Study on HNF1B-Related Nephropathy in Chinese Children","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eThe clinical validation and molecular profiling of renal cysts during prenatal or pediatric evaluations represent important elements in the differential diagnostic framework for CAKUT, which accounts for 20\u0026ndash;30% of prenatal congenital malformations and affects approximately 3\u0026ndash;6 in 1000 live births\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. Among monogenic CAKUT etiologies, \u003cem\u003eHNF1B\u003c/em\u003e mutations constitute a predominant genetic cause, with this locus demonstrating particular susceptibility to pathogenic \u003cem\u003ede novo\u003c/em\u003e variants\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. As a pivotal transcription factor governing embryonic organogenesis, particularly in the kidney and pancreas, \u003cem\u003eHNF1B\u003c/em\u003e mutation is initially found to be responsible for Renal Cysts and Diabetes syndrome (RCAD; OMIM #137920) or Maturity-Onset Diabetes of the Young 5 (MODY5; OMIM #604284), following an autosomal dominant inheritance pattern\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. Of clinical significance, since glucose homeostasis abnormalities in HNF1B syndrome remain pharmacologically modifiable, kidney failure has emerged as the predominant prognostic determinant\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. Therefore, systematic characterization of HNF1B genotype-phenotype relationships, particularly focusing on renal manifestations, is crucial for both mechanistic understanding and clinical management.\u003c/p\u003e\u003cp\u003eAs a member of the homeodomain-containing transcription factor superfamily, HNF1B comprises an amino-terminal dimerization domain, a bipartite POU-type DNA-binding domain, and a carboxy-terminal transactivation domain interacting with key coactivators and corepressors in organogenesis and homeostasis\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. Specifically for the kidney development, HNF1B plays critical roles in multiple morphogenetic processes, including ureteric bud branching, nephron patterning, and tubulogenesis. HNF1B absence prevents mesenchymal to epithelial transition, ultimately leading to renal hypoplasia\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. When \u003cem\u003eHnf1b\u003c/em\u003e is deleted during the tubular elongation phase, a multicystic phenotype emerges, accompanied by downregulation of cystogenesis-related genes, such as \u003cem\u003ePkd2\u003c/em\u003e, \u003cem\u003ePkhd1\u003c/em\u003e, and \u003cem\u003eUmod\u003c/em\u003e\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. For postnatal kidney, HNF1B is involved in tissue maintenance and responsible for metabolism and solute transport partially through regulating the expression of FXYD2, a key regulator for renal magnesium (Mg\u0026sup2;⁺) reabsorption\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. Consequently, \u003cem\u003eHNF1B\u003c/em\u003e mutations can disrupt electrolyte homeostasis, another observable clinical phenotype. Notably, not all HNF1B abnormalities are associated with electrolyte disorder. \u003cem\u003eIn vitro\u003c/em\u003e studies have shown that specific mutations modify the expression networks of downstream target genes, suggesting a potential mechanism underlying phenotypic heterogeneity\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. Thus, exploring the correlation between \u003cem\u003eHNF1B\u003c/em\u003e mutation types and clinical phenotypes would facilitate the establishment of a precise diagnostic system for \u003cem\u003eHNF1B\u003c/em\u003e-related disorders.\u003c/p\u003e\u003cp\u003eIn this study, a pediatric cohort comprising 26 children with HNF1B-related disorders was established using the CCGKDD. After systematically analyzing their phenotypic and genotypic characteristics, we found that the 17q12 deletion cohort exhibited earlier onset of fetal renal phenotypic abnormalities(median age: 0 vs 1 year 11 months, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.121), whereas the \u003cem\u003eHNF1B\u003c/em\u003e mutation group displayed more severe renal functional deterioration at final follow-up (latest estimated glomerular filtration rate (eGFR) : 85 vs 45.6 mL/min/1.73m\u0026sup2;, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.11). These phenotypic divergences likely stem from distinct genetic mechanisms, including transcription factor dominant-negative effects and haploinsufficiency-mediated pathways. Moreover, for \u003cem\u003eHNF1B\u003c/em\u003e-mutated kidney transplant recipients developing tacrolimus-associated hyperglycemia, conversion to cyclosporine A or sirolimus represents an effective therapeutic strategy.\u003c/p\u003e"},{"header":"2. Participants and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Subjects\u003c/h2\u003e\u003cp\u003eA total of twenty-six Chinese pediatric patients with \u003cem\u003eHNF1B\u003c/em\u003e mutations from CCGKDD were enrolled. The inclusion criteria required: (1) molecular diagnosis of \u003cem\u003eHNF1B\u003c/em\u003e with pathogenic variants by sequencing, and (2) comprehensive clinical documentation. Detailed phenotypic data including renal manifestations, diabetes status (in probands or family members), and other clinical features, were collected from institutional medical records. All the enrolled cases were distributed in four centers, scattered over thirteen province/municipalities (seventeen cities) in China.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Clinical diagnosis\u003c/h2\u003e\u003cp\u003eAll patients enrolled in this study were primarily diagnosed by pediatric nephrologists. CAKUT, pancreatic and hepatobiliary tract malformations were defined as structural abnormalities in the imaging tests, including ultrasonography, X-ray fluoroscopy, computed tomography, or magnetic resonance imaging. Hyperuricemia in children/adolescents was defined as serum uric acid levels\u0026thinsp;\u0026ge;\u0026thinsp;5.5 mg/dL\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. Electrolyte abnormalities were diagnosed when abnormal levels were persisted or necessitated intervention. Hypomagnesemia was defined as serum magnesium concentrations\u0026thinsp;\u0026lt;\u0026thinsp;0.65 mmol/L. Diabetes was diagnosed as patients with chronic hyperglycemia meeting the following criteria repeatedly: (1) fasting plasma glucose level of \u0026ge;\u0026thinsp;126 mg/dL; (2) 2-h post-load glucose\u0026thinsp;\u0026ge;\u0026thinsp;200 mg/dL during a 75 g oral glucose tolerance test; (3) random plasma glucose\u0026thinsp;\u0026ge;\u0026thinsp;200 mg/dL\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. The estimated glomerular filtration rate (eGFR) was calculated from serum creatinine and body height according to the Schwartz formula\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. Chronic kidney disease (CKD) stages I\u0026ndash;V were defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group guidelines\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. Genital abnormalities and neurological abnormalities were diagnosed by primary doctors.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Genetic analysis\u003c/h2\u003e\u003cp\u003eGenetic studies for probands and available first-degree relatives included whole exome sequencing (WES), whole genome sequencing (WGS), gene copy number variation (CNV), quantitative polymerase chain reaction (qPCR) or kidney panel examination. Peripheral venous blood (2\u0026ndash;4 mL) was collected to extract genomic DNA using the Blood genome column medium extraction kit following the manufacturer\u0026rsquo;s instructions (Kangweishiji, China). All sequencing was performed by the Beijing Chigene Translational Medicine Research Center Co., Ltd., Beijing, China. The paired-end reads were aligned to the Ensembl GRCh37/hg19 reference genome using Burrows-Wheeler Aligner (BWA). Single nucleotide variants (SNVs) and small insertions/deletions (Indels) were called using the Genomic Analysis Toolkit (GATK) software (version 4.1.7). Copy number variant (CNV) were detected using the Exon Depth algorithm. Sequence alterations were checked against published polymorphism/mutations and evaluated for conservation across species. Pathogenicity analysis of variants was performed according to the American College of Medical Genetics and Genomics (ACMG) practice guidelines. Bidirectional Sanger sequencing was performed to validate the screened variants. Multiple computational software (Human Splicing Finder 3.1, PolyPhen-2, Mutation Taster, and VarCards) were used to evaluate the pathogenic effects of variants.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4 Molecular modeling and structural analysis\u003c/h2\u003e\u003cp\u003eThe 3D modeled structures of HNF1B protein for the wild-type and mutant types were prepared using homology modeling in SWISS-MODEL. Structural analysis was analyzed and visualized using the PyMOL software.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e2.5 Statistical analysis\u003c/h2\u003e\u003cp\u003eContinuous variables are presented as median (range). Mann-Whitney test was used for comparison of non-normal distributed continuous variables between the two groups, while Fisher exact probability test was used for categorical variables. Kaplan-Meier survival curves were employed to compare the renal survival using end-stage renal disease (ESRD) as an end point. A \u003cem\u003ep\u003c/em\u003e value\u0026thinsp;\u0026lt;\u0026thinsp;0.1 was considered to be statistically significant. IBM SPSS Statistics 25 software (IBM Co., Armonk, NY, USA) was used for all calculation.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e3.1 Clinicopathological analysis of renal disorders\u003c/h2\u003e\u003cp\u003e26 HNF1B-associated pediatric patients consisted of 10 males, 14 females, and 2 cases with unrecorded sex. The median age at disease onset was birth (range: birth-5.3 years), whereas the median age at genetic diagnosis was 5.8 years (range: 1.3\u0026ndash;7.5 years).\u003c/p\u003e\u003cp\u003eCorresponding to median disease onset at birth, 15 cases exhibited abnormal renal findings on prenatal ultrasound. The spectrum included: hyperechoic kidneys (HE; 5/15), hydronephrosis (HN; 3/15), renal dysplasia (3/15), cysts (3/15), abnormal amniotic fluid volume (3/15), and solitary kidney (1/15). Notably, 3 cases presented with two concurrent abnormalities (primarily involving amniotic fluid volume). Transitioning to postnatal evaluation, 24 cases universally demonstrated renal abnormalities on ultrasound. And the postnatal phenotype diverged from prenatal findings, with cysts emerging as the dominant feature (12/24), followed by MCDK (9/24) and renal dysplasia (5/24; defined by loss of corticomedullary differentiation and/or increased echogenicity). Rare manifestations comprised ectopic kidney, duplex kidney, vesicoureteral reflux (VUR), and nephrocalcinosis, each observed in one case. This phenotypic evolution suggests progressive renal pathology from fetal to childhood stages in \u003cem\u003eHNF1B\u003c/em\u003e-related nephropathy (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePhenotypes and genetypes of the patients.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"10\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eCase\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003esex\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eFamily history\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003ePrenatal renal assessment\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003ePostnatal renal phenotype\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eExtral-renal phenotype\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eHNF1B gene mutation (accession no: NM_000458) or 17q12 deletion (assembly: GRCh37)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eMutation origin\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eonset\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eGD\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4y\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHE (B)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCyst (B), CKD1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e17q12 deletion; chr17: 34815551\u0026ndash;36249430 (1.4 Mb)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1y1m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003efather: HN (R) and Cyst (B)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eDysplasia (L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003edysplasia (L), Cyst (R)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eMD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e17q12 deletion; chr17: 34536497\u0026ndash;36388301 (1.85 Mb)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003ePaternal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5y9m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHE (B)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMCDK (B), HUA, CKD 2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eDD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e17q12 deletion; NA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8y5m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8y5m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003emother: Cyst and stones (B)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003edysplasia (B), HE (B), HUA, proteinuria, CKD 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ec.578 T\u0026thinsp;\u0026gt;\u0026thinsp;C (exon 3), p.M193T\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eMaternal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2y8m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003edysplasia (B), Oligohydramnios\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMCDK (B), HN (B), HUA, CKD4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eDD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e17q12 deletion; chr17: 34775520\u0026ndash;36278036 (1.5Mb)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eMaternal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHN (L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCyst (B), HN (L), CKD 1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e17q12 deletion; chr17: 34765237\u0026ndash;36276584 (1.52Mb)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDe novo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003edysplasia(B)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003edysplasia (B), HE (B), HUA, CKD 5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ec.441G\u0026gt;T (exon 2), p.Q147H\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDe novo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11y9m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11y10m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCyst (L), MCDK (R), proteinuria, HUA, CKD 4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ec.1339\u0026thinsp;+\u0026thinsp;5 (IVS6) G\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDe novo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1y3m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1y4m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eOligohydramnios\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMCDK (L), HE (B), HUA, CKD 2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e17q12 deletion; chr17: 34836666\u0026ndash;36241241 (1.4Mb)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDe novo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMCDK (B), HE (B), NC (B), HUA, CKD 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ec.493C\u0026gt;G(exon 2), p.R165G\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDe novo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7y9m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7y9m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMCDK (R), HUA, CKD 5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eDD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e17q12 deletion; chr17: 34495987\u0026ndash;36293050 (1.8Mb)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eMaternal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1y6m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHN\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMCDK (L), HUA, CKD 1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eEP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e17q12 deletion; chr17: 34581399\u0026ndash;36347081 (1.77Mb)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDe novo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7y6m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7y6m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eHN (L), dysplasia (R), VUR (B)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ec.364G\u0026gt;T(exon 2), p.A122S\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003ePaternal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5y11m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5y11m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCyst (B), HE (B), CKD 2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e17q12 deletion; chr17: 34493374\u0026ndash;36104875 (1.61Mb)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCyst (B), proteinuria\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eelevated ALT/AST\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e17q12 deletion; chr17:\u003c/p\u003e\u003cp\u003e34842526\u0026ndash;36104883 (NA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3y6m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13y10m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eHE (B), HUA ,\u003c/p\u003e\u003cp\u003eCKD 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ec.662A\u0026gt;T(exon 3), p.D221V\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003ePaternal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6y3m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSK (R)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003edysplasia (L), EK (L), CKD 2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e17q12 deletion; chr17:\u003c/p\u003e\u003cp\u003e34806197\u0026ndash;36104875 (1.3Mb)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDe novo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2y10m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003efather: Cyst (B); grandmother: CKD 5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCyst(B)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMCDK(B), HUA, CKD 2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHypoMg\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ec.541C\u0026gt;T(exon 2), p.R181X\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003ePaternal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCyst (R)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMCDK(L), Cyst (R), HUA, CKD 2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ec.544\u0026thinsp;+\u0026thinsp;3_544\u0026thinsp;+\u0026thinsp;6 (IVS2) delAAGT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eMaternal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eunknown\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003emother: Cyst (B)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHE (B), HN (R)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ec.1006del(exon 4), p.H336Tfs*40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eMaternal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eunknown\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHE (B), hydramnios\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e17q12 deletion;chr17:\u003c/p\u003e\u003cp\u003e34434562\u0026ndash;36252160 (1.82Mb)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDe novo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8y5m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8y5m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCyst (B), CKD 5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ec.1390\u0026ndash;1405 dup (exon 7), p.L469Rfs*87\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eMaternal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2y\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15y\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003efather: Cyst (B); grandfather: DM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCyst (B), HUA, CKD5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eDM, elevated ALT/AST\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e17q12 deletion; chr17:\u003c/p\u003e\u003cp\u003e34836666\u0026ndash;36225059 (1.26Mb)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003ePaternal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6y10m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6y10m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCyst (B); HUA,\u003c/p\u003e\u003cp\u003eCKD 5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eDM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e17q12 deletion; chr17:\u003c/p\u003e\u003cp\u003e34497248\u0026ndash;36104875 (1.61Mb)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDe novo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6y9m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCyst\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCyst (B); CKD 1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003ePC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e17q12 deletion; chr17:\u003c/p\u003e\u003cp\u003e34806197\u0026ndash;36104875 (1.3Mb)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDe novo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6y9m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHE (B)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCyst (B), duplicate kidney (L); CKD 1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e17q12 deletion; chr17:\u003c/p\u003e\u003cp\u003e34842543\u0026ndash;36104875 (1.26Mb)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDe novo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eDifferent from the cyst-dominant pathology observed on imaging, renal functional outcomes in HNF1B-related children demonstrated marked heterogeneity. Hyperuricemia was present in 58.3% (14/24) of patients, while microalbuminuria, a marker of early glomerular injury, was detected in 12.5% (3/24). Longitudinal follow-up (median: 15 months; range: 6\u0026ndash;31 months) revealed that nearly half of the cohort (10/21, 47.6%) progressed to advanced CKD (stages 3\u0026ndash;5). Among the 5 patients who progressed to CKD 5, 3 underwent successful renal transplantation with stable graft function. 1 developed post-transplant hyperglycemia managed by switching immunosuppression from tacrolimus to cyclosporine A, indicating cyclosporine A may offer superior glycemic control in pediatric \u003cem\u003eHNF1B\u003c/em\u003e associated nephropathy patients with post-transplant hyperglycemia. Meanwhile, two remained on regular peritoneal dialysis.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e3.2 Extrarenal symptoms\u003c/h2\u003e\u003cp\u003eGiven \u003cem\u003eHNF1B\u003c/em\u003e's critical role as a transcription factor in multi-organ development, extrarenal manifestations exhibit a distinct phenotypic pattern, primarily including pancreatic hypoplasia with exocrine dysfunction. Notably, while pancreatic developmental anomalies are common, the clinical onset of associated diabetes occurs significantly later than renal manifestations. This temporal discrepancy suggests either differential organ sensitivity to \u003cem\u003eHNF1B\u003c/em\u003e deficiency or, more likely, divergent developmental timing of \u003cem\u003eHNF1B\u003c/em\u003e expression across organs.\u003c/p\u003e\u003cp\u003eAmong our cohort, diabetes mellitus developed in 2 patients despite normal pancreatic morphology. Conversely, 3 patients maintained normal blood glucose levels with pancreatic developmental anomalies, including 2 hypoplastic pancreas and 1 multiple pancreatic cyst. Additionally, 2 showed elevated transaminases, 1 had hypomagnesemia, and 5 presented with neurological developmental abnormalities, including 1 epilepsy, 1 cerebral hypoplasia, and 3 psychomotor retardation.\u003c/p\u003e\u003cp\u003eNotably, because of age-dependent penetrance, cryptic clinical features (e.g., asymptomatic hypomagnesemia and mildly elevated transaminases), and diagnostic limitations (e.g., routine pediatric exams lacking pancreatic/reproductive assessments), the extrarenal symptoms in our cohort may be underdiagnosed. To improve patients' quality of life and better characterize genotype-phenotype correlations, enhanced emphasis for extrarenal symptoms on further follow-up may be warranted in \u003cem\u003eHNF1B\u003c/em\u003e-related disorders.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003e3.3 Genotype\u003c/h2\u003e\u003cp\u003eGenetic studies revealed total gene deletion of 17q12 in 16 patients (61.5%), 6 missense mutation (23.1%), 2 splice mutation (7.7%), 1 deletion and 1 duplicate mutation (7.7%), among which c.1390-1405dup in exon 7 was unreported (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). Notably, although c.1390-1405dup caused a frameshift translation due to a non-triplet 16 base pair (bp) repeat, it did not lead to premature termination. Instead, it resulted significant changes of the last 89aa, corresponding to C-terminal transactivation domain (p.L469Rfs*87) and likely disrupting the interaction with coactivator/corepressor (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb). Interestingly, 3D protein structure modeling suggested that beyond the local structural disruption after amino acid 469, spatial rearrangements also occur in regions with unchanged amino acid composition, indicating that the mutation may induce allosteric effects through long-range conformational propagation and further affecting overall protein stability or function (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec). Moreover, the proband inherited the mutation maternally, with the mother showing no phenotypic abnormalities. In contrast, the proband exhibited rapid renal deterioration leading to CKD 5 and is currently managed with peritoneal dialysis.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eCascade screening of parental DNA in 22 patients identified \u003cem\u003eHNF1B\u003c/em\u003e mutation transmission in 11 families, without significant parent-of-origin effect bias (6/11 showing maternal and 5/11 paternal inheritance). Five parental mutation carriers exhibited clinical symptoms of renal cysts. Among these inherited mutations, the molecular subtypes were whole gene deletion (4/11), missense mutation (3/11), splice site mutation (1/11), nonsense mutation (1/11), and indel mutation (2/11). The remaining 50% harbored \u003cem\u003ede novo HNF1B\u003c/em\u003e mutations, highlighting the significant contribution of spontaneous genetic alterations in this cohort. Among these, 8/11 constituted complete gene deletions (17q12 deletion), 2/11 missense, and 1/11 spice mutation.\u003c/p\u003e\u003cp\u003eOverall, 17q12-related \u003cem\u003eHNF1B\u003c/em\u003e whole gene deletions were the predominant type in our \u003cem\u003eHNF1B\u003c/em\u003e mutation spectrum, with no significant difference in the proportion of inherited versus \u003cem\u003ede novo\u003c/em\u003e mutations. Additionally, our study also confirmed that \u003cem\u003eHNF1B\u003c/em\u003e mutations remained highly clustered in the known hotspots of exon 2 and exon 3.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003e3.4 Genotype-Phenotype Correlations\u003c/h2\u003e\u003cp\u003eBased on the reported mutated genotype dichotomy of \u003cem\u003eHNF1B\u003c/em\u003e, the study cohort was stratified into two groups based on genetic testing results: the 17q12 deletion group (16/26) and the \u003cem\u003eHNF1B\u003c/em\u003e mutation group (10/26). Our findings demonstrated a higher prevalence of prenatal renal phenotypic abnormalities in the 17q12 deletion group compared to the \u003cem\u003eHNF1B\u003c/em\u003e group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.300), suggesting an earlier onset of renal manifestations in the former. During the follow-up period (median follow-up duration: 27.9 months in 16 pediatric patients), the 17q12 deletion group exhibited a faster eGFR decline per unit time compared to the \u003cem\u003eHNF1B\u003c/em\u003e group (0.71 [-0.51, 3.83] vs. 0 [-0.95, 4.24] mL/min/1.73m\u0026sup2;/year, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.227). The kidney survival rates at the 4-year and 12.5-year follow-up were 80% and 25%, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). However, at the latest follow-up assessment, the median eGFR in the 17q12 deletion group was significantly higher than that in the \u003cem\u003eHNF1B\u003c/em\u003e group (85 [10\u0026ndash;135] vs. 45.66 [10-87.7] mL/min/1.73m\u003csup\u003e2\u003c/sup\u003e, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.110) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). At the latest follow-up, a greater proportion of patients in the \u003cem\u003eHNF1B\u003c/em\u003e group had progressed to CKD stages 3\u0026ndash;5 than those in the 17q12 deletion group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.08), indicating more severe postnatal renal dysfunction in \u003cem\u003eHNF1B\u003c/em\u003e variant carriers. All five cases with neurological abnormalities occurred in the 17q12 deletion group, while no neurodevelopmental disorders were observed in the \u003cem\u003eHNF1B\u003c/em\u003e group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.116). This phenotypic distinction may reflect additional neurodevelopmental genes within the 17q12 deletion region, although statistical significance was not reached. No statistically significant differences were observed between the two genotypes in the distribution of secondary manifestations including hyperuricemia, hypomagnesemia, diabetes mellitus, pancreatic abnormalities, hepatic dysfunction, or genitourinary malformations(Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eComparison of clinial phenotypes between patients with 17q12 deletions and \u003cem\u003eHNF1B\u003c/em\u003e variants\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharacteristics\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17q12 deletion\u003c/p\u003e\u003cp\u003e(16)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eHNF1B\u003c/em\u003e variant\u003c/p\u003e\u003cp\u003e(10)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (months) at onset\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0\u0026ndash;93)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e23 (0-141)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.121\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (months) at GD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e69 (2-180)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e90 (5-166)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.325\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrenatal ultrasound abnormalities\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11/16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4/10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.300\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLatest eGFR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e85 (10\u0026ndash;135)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e45.6 (10-87.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.110\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eeGFR decline rate (mL/min/1.73m\u0026sup2;/year)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.71 (-0.51, 3.83)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (-0.95, 4.24)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.277\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e\u003cp\u003eLatest CKD Stage\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e0.080\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCKD stage 1\u0026ndash;2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9/13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2/8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCKD stage 3\u0026ndash;5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4/13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6/8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHyperuricemia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6/15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4/9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHypomagnesemia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1/8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.364\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiabetes mellitus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2/11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0/9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.479\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePancreatic abnormolities\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2/11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1/7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLiver abnormalities\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0/8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.515\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGenital abnormalities\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0/6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0/5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNeurological abnormality\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5/14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0/9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.116\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eBased on the transcription factor characteristics of the \u003cem\u003eHNF1B\u003c/em\u003e, several cohorts have adopted a mutated genotype dichotomy (distinguishing between intragenic \u003cem\u003eHNF1B\u003c/em\u003e mutations and 17q12 deletion spanning 15 genes including \u003cem\u003eHNF1B\u003c/em\u003e) to investigate genotype-phenotype correlations. While convergent themes exist across studies, discrepancies in certain aspects also emerge, potentially reflecting variations in cohort characteristics and analytical approaches. Ulinski et al. found no difference in renal function or severity of renal morphologic lesions between patients with \u003cem\u003eHNF1B\u003c/em\u003e deletions and point mutations\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. And Okorn et al. identified a maternal transmission bias and reported that renal cyst progression was correlated positively with declining renal function, early-onset ESRD (before 2 years of age) was associated with bilateral dysplasia. Notably, both outcomes occurred independently of the mutant genotype\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn this study, we found that the 17q12 deletion group exhibited a higher prevalence of fetal renal abnormalities compared to \u003cem\u003eHNF1B\u003c/em\u003e mutation group, suggesting earlier onset of kidney manifestations in deletion carriers. A cohort study focusing on 17q12 deletions reported a 65% prevalence of prenatal renal ultrasound abnormalities, which was close to the 68% in our study\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. Mechanistically, the 17q12 deletion results in \u003cem\u003eHNF1B\u003c/em\u003e haploinsufficiency, probably reducing its expression below the critical threshold required for normal nephrogenesis, a phenomenon consistent with the exquisite dosage sensitivity of transcription factors during embryonic cell fate determination\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. In contrast, \u003cem\u003eHNF1B\u003c/em\u003e missense/truncating mutations may retain partial protein activity, which could sustain early renal development through the compensation by other proteins, such as HNF1A. Moreover, a recent study utilizing human induced pluripotent stem cells (hiPSCs) demonstrated that precisely timed attenuation of Wnt/β-catenin signaling was required to achieve optimal HNF1B activation, which was necessary for proper mesenchymal-epithelial transition (MET) during kidney tubule formation, highlighting the importance of \u003cem\u003eHNF1B\u003c/em\u003e expression levels\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eOn the other hand, our longitudinal follow-up revealed that patients in the \u003cem\u003eHNF1B\u003c/em\u003e mutation group progressed to advanced CKD stages (3\u0026ndash;5) more frequently than those with 17q12 deletions, suggesting accelerated postnatal renal functional decline in mutation carriers, consistent with conclusion in that compared with the patients with mutations, those with HNF1B deletion less had CKD 3\u0026ndash;4/ESRD at diagnosis and in the long term\u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. This phenotypic divergence may stem from dominant-negative effects exerted by mutant HNF1B proteins, with distinct molecular consequences based on mutation localization. Specifically, when mutations occur within the DNA-Binding domain, the mutant protein retains dimerization capacity but impairs DNA recognition. For transactivation domain (TAD) -localized variants, mutant proteins maintain DNA binding capability but fail to recruit coactivators or coinhibitor due to disrupted interaction interfaces. In either case, these mutant proteins with compromised functions competitively occupy regulatory elements, progressively impairing wild-type protein function through a dominant-negative effect. Notably, the inhibitory effect may exhibit gradually intensified characteristics as the mutant protein proportion accumulates over time. In our cohort, no specific mutational loci within the \u003cem\u003eHNF1B\u003c/em\u003e gene demonstrated preferential association with the progression to advanced kidney disease.\u003c/p\u003e\u003cp\u003eNotably, patient 22 harbored a novel \u003cem\u003eHNF1B\u003c/em\u003e mutation (c.1390-1405dup, p.L469Rfs*87) in exon 7, different from the hotspot mutation (exon 2 and exon 3) and representing the first reported duplication affecting the C-terminal TAD. Clinically, the patient exhibited rapidly progressive renal phenotype, eventually developing CKD 5, requiring regular peritoneal dialysis and awaiting renal transplantation. The mutation was maternally inherited, but the mother remained asymptomatic, possibly due to incomplete penetrance, consistent with previous observation that the phenotype can vary considerably among persons carrying the same \u003cem\u003eHNF1B\u003c/em\u003e mutation, even among members of the same family\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. Thus, prenatal screening for females from \u003cem\u003eHNF1B\u003c/em\u003e-mutated families should integrate \u0026ldquo;genetic testing plus imaging assessment plus genetic counseling\u0026rdquo; to confirm mutation carriage, rather than absolutely predict phenotypes. Clinically, it is essential to emphasize to parents the uncertainty of penetrance and advocate for long-term postnatal monitoring combined with environmental interventions (e.g., weight control, low-sugar diet) to mitigate the risk of phenotypic expression.\u003c/p\u003e\u003cp\u003eAlthough this study primarily focused on renal phenotypes associated with \u003cem\u003eHNF1B\u003c/em\u003e mutations, it was important to recognize that \u003cem\u003eHNF1B\u003c/em\u003e also serves as a critical transcriptional regulator of pancreatic development and function, whose mutation could develop early-onset diabetes. Given that a subset of pediatric HNF1B patients progress to CKD 5, renal transplantation remains the preferred renal replacement therapy. Thus, the impact of immunosuppressant selection on post-transplantation glycemic control requires heighted attention. In this study, three post-transplant children initially received tacrolimus for rejection prophylaxis, but one developed hyperglycemia, which resolved after switching from tacrolimus to cyclosporine A (CsA), both of which are cornerstone agents in post-transplant immunosuppression, although tacrolimus is often favored in pediatric renal transplantation due to its superior efficacy and a more favorable side-effect profile. Mechanistically, Tacrolimus impairs glucose metabolism by inhibiting the calcineurin-NFAT pathway, which disrupts β-cell insulin secretion, activates mTOR signaling, leads to peripheral insulin resistance and reduces glucose uptake\u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. A Meta-analysis showed that tacrolimus use was associated with a higher incidence of new-onset diabetes than CsA after transplantation (NODAT)\u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. Therefore, based on these findings, the dual risk of \u003cem\u003eHNF1B\u003c/em\u003e-related diabetes and CNI-induced hyperglycemia necessitates a proactive, individualized immunosuppressive strategy in transplant recipients.\u003c/p\u003e\u003cp\u003eIn conclusion, this study demonstrates that the 17q12 deletion group exhibited earlier fetal renal phenotypes, while the \u003cem\u003eHNF1B\u003c/em\u003e mutation group showed worse renal function at follow-up end, which was probably linked to genetic mechanisms including transcription factor haploinsufficiency and dominant-negative effects. For \u003cem\u003eHNF1B\u003c/em\u003e-mutated patients post-kidney transplantation, if hyperglycemia develops during tacrolimus therapy, substitution with cyclosporine A or mTOR inhibitors (e.g., sirolimus) is preferred. The primary limitation of this study is the small sample size, coupled with incomplete assessment of extrarenal phenotypes in certain cases, which may have introduced bias in phenotype analysis. Future studies with larger sample sizes, comprehensive phenotypic profiling, and extended follow-up durations are essential to fully characterize the clinical landscape of \u003cem\u003eHNF1B\u003c/em\u003e-related disorders. Such investigations will facilitate the development of evidence-based prognostic interventions, thereby enhancing our ability to inform clinical management and improve outcomes for affected individuals.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCAKUT: congenital anomalies of the kidney and urinary tract; CCGKDD: Chinese Children Genetic Kidney Disease Database; MCDK: multicystic dysplastic kidney; eGFR: estimated glomerular filtration rate; CKD: Chronic kidney disease; ESRD: end-stage renal disease; TAD: transactivation domain; CsA: cyclosporine A; GD: genetic diagnosis; y: year, m: month. B: bilateral. L: left. R: right. HN: hydronephrosis. Cyst: multiple renal cysts. CKD: chronic kidney diease. DM: diabetes mellitus. MCDK: multicystic dysplastic kidney. HUA: hyperuricaemia. HE: renal parenchymal hyperechogenicity. NC: nephrocalcinosis. VUR: vesicoureteral reflux. SK: solitary kidney. EK: ectopic kidney. ALT: alanine transaminase. AST: aspartate transaminase. PC: pancreatic cyst. NA: not available. DD: developmental delay. MD: myelination dysplasia. EP: epilepsy. SP: small pancreas.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the [Ethics Committee of Wuhan Children\u0026rsquo;s Hospital] (Approval number: [2024R141-E01]).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eWritten informed consent was obtained from all participants. In accordance with federal and institutional guidelines, informed consent was obtained from the legal guardians for pediatric patients younger than the age of 16, while informed consent was obtained directly from pediatric patients aged over 16 years themselves.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the finding of this study are available from the corresponding author upon reasonable request. The ClinVar accession number for the present HNF1B variants are VCV004071464.1, VCV000635616.9, VCV000635666.10, VCV000635668.11, VCV000372381.24, VCV004071465.1, VCV004071463.1, VCV004071466.1, and VCV000805639.10.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by Construction Project of Research Division of Children\u0026apos;s Kidney Disease of Wuhan Children\u0026apos;s Hospital (2022FEYJS003), Knowledge and Innovation Project of Wuhan Science and Technology Bureau (2023020201010197), Hubei Provincial Health Commission Joint Fund Project (WJ2023M149), and Shanghai \u0026ldquo;Rising Stars of Medical Talents\u0026rdquo; Youth Development Program (SHWSRS(2023)_070).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eAll authors contributed to the intellectual content of this manuscript and approved the final manuscript as submitted. HZ collected data and drafted the manuscript with the help of CW, XJ and XG, HY and PL and LH performed gene analysis and generated figures, XT, JL, RD and AZ interpreted the data, QS, XW and HX revised the article for important intellectual content. All authors have critically read and approved the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; We thank all patients and their families for their participation in this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKolvenbach, C.M., S. Shril, and F. 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Souza, \u003cem\u003ePharmacotherapy for hyperuricemia in hypertensive patients.\u003c/em\u003e Cochrane Database Syst Rev, 2017. 4(4): p. Cd008652.\u003c/li\u003e\n\u003cli\u003eSeino, Y., et al., \u003cem\u003eReport of the committee on the classification and diagnostic criteria of diabetes mellitus.\u003c/em\u003e J Diabetes Investig, 2010. 1(5): p. 212-28.\u003c/li\u003e\n\u003cli\u003eSchwartz, G.J., L.P. Brion, and A. Spitzer, \u003cem\u003eThe use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents.\u003c/em\u003e Pediatr Clin North Am, 1987. 34(3): p. 571-90.\u003c/li\u003e\n\u003cli\u003eStevens, P.E. and A. Levin, \u003cem\u003eEvaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline.\u003c/em\u003e Ann Intern Med, 2013. 158(11): p. 825-30.\u003c/li\u003e\n\u003cli\u003eUlinski, T., et al., \u003cem\u003eRenal phenotypes related to hepatocyte nuclear factor-1beta (TCF2) mutations in a pediatric cohort.\u003c/em\u003e J Am Soc Nephrol, 2006. 17(2): p. 497-503.\u003c/li\u003e\n\u003cli\u003eOkorn, C., et al., \u003cem\u003eHNF1B nephropathy has a slow-progressive phenotype in childhood-with the exception of very early onset cases: results of the German Multicenter HNF1B Childhood Registry.\u003c/em\u003e Pediatr Nephrol, 2019. 34(6): p. 1065-1075.\u003c/li\u003e\n\u003cli\u003eVerscaj, C.P., et al., \u003cem\u003eCharacterization of the prenatal renal phenotype associated with 17q12, HNF1B, microdeletions.\u003c/em\u003e Prenat Diagn, 2024. 44(2): p. 237-246.\u003c/li\u003e\n\u003cli\u003eRice, A.M. and A. McLysaght, \u003cem\u003eDosage sensitivity is a major determinant of human copy number variant pathogenicity.\u003c/em\u003e Nat Commun, 2017. 8: p. 14366.\u003c/li\u003e\n\u003cli\u003eDubois-Laforgue, D., et al., \u003cem\u003eDiabetes, Associated Clinical Spectrum, Long-term Prognosis, and Genotype/Phenotype Correlations in 201 Adult Patients With Hepatocyte Nuclear Factor 1B (HNF1B) Molecular Defects.\u003c/em\u003e Diabetes Care, 2017. 40(11): p. 1436-1443.\u003c/li\u003e\n\u003cli\u003eMadariaga, L., et al., \u003cem\u003eVariable phenotype in HNF1B mutations: extrarenal manifestations distinguish affected individuals from the population with congenital anomalies of the kidney and urinary tract.\u003c/em\u003e Clin Kidney J, 2019. 12(3): p. 373-379.\u003c/li\u003e\n\u003cli\u003eRodriguez-Rodriguez, A.E., et al., \u003cem\u003eInhibition of the mTOR pathway: A new mechanism of \u0026beta; cell toxicity induced by tacrolimus.\u003c/em\u003e Am J Transplant, 2019. 19(12): p. 3240-3249.\u003c/li\u003e\n\u003cli\u003eOliveras, L., et al., \u003cem\u003eImmunosuppressive drug combinations after kidney transplantation and post-transplant diabetes: A systematic review and meta-analysis.\u003c/em\u003e Transplant Rev (Orlando), 2024. 38(3): p. 100856.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"HNF1B, 17q12 deletion, CAKUT, chronic kidney disease, children","lastPublishedDoi":"10.21203/rs.3.rs-7138364/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7138364/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eHepatocyte nuclear factor 1β (\u003cem\u003eHNF1B\u003c/em\u003e) pathogenic variants constitute a major genetic contributor to congenital anomalies of the kidney and urinary tract (CAKUT), with patients simultaneously exhibiting distinct extrarenal features. Among these clinical manifestations, renal disease progression is crucial for long-term outcomes, needing comprehensive evaluation.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eUsing the Chinese Children Genetic Kidney Disease Database (2017\u0026ndash;2024), we analyzed 26 pediatric \u003cem\u003eHNF1B\u003c/em\u003e cases to characterize renal phenotypes and genotype correlations.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eAll patients exhibited abnormal renal phenotypes at diagnosis: renal cysts (50%) and multicystic dysplastic kidney (MCDK) (37.5%). Genetic analysis revealed 16 patients (61.5%) had a 17q12 deletion including \u003cem\u003eHNF1B\u003c/em\u003e gene, while the remaining carried \u003cem\u003eHNF1B\u003c/em\u003e intragenic mutations, including a novel c.1390-1405dup. Comparing phenotypic trajectories, 17q12 deletion cases showed earlier renal phenotype onset (median age : 0 vs 1 year 11 months, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.121), while \u003cem\u003eHNF1B\u003c/em\u003e variants showed faster renal function deterioration (latest eGFR: 85 vs 45.6 mL/min/1.73m\u0026sup2;, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.11). Three of five CKD 5 children underwent kidney transplantation before 15; one developed reversible tacrolimus-induced hyperglycemia.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThese results demonstrated genotype-phenotype divergence: 17q12 deletion may promote developmental renal anomalies via haploinsufficiency, while \u003cem\u003eHNF1B\u003c/em\u003e variants likely accelerate tubular dysfunction through dominant-negative transcriptional dysregulation. Prenatal counseling, genotype-specific monitoring, and renal monitoring for affected families are recommended.\u003c/p\u003e","manuscriptTitle":"From Mutation to Symptoms: A Multi-Center Study on HNF1B-Related Nephropathy in Chinese Children","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-17 14:17:20","doi":"10.21203/rs.3.rs-7138364/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-01T07:12:39+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-28T23:47:38+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-25T19:39:20+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-22T12:48:11+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-21T09:39:20+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-20T18:11:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"219732198768828983649252148569619129125","date":"2025-08-13T19:31:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"56004506437919735582526073174442541502","date":"2025-08-13T15:28:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"76716483658221357146102968605381246032","date":"2025-08-13T11:13:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"144368077899536824889170000776035066132","date":"2025-08-13T03:52:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"272396900816258177326630380872527198869","date":"2025-08-12T09:14:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"151556694254432468103824335990800310051","date":"2025-08-11T11:45:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"181383030822419342863815008914143362889","date":"2025-08-11T11:31:34+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-08T14:58:26+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-08T14:55:30+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-07-31T10:13:30+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-31T08:59:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Nephrology","date":"2025-07-31T08:25:53+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b6313368-7198-4d90-b689-d0534a0f4fe4","owner":[],"postedDate":"August 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-12-29T16:00:25+00:00","versionOfRecord":{"articleIdentity":"rs-7138364","link":"https://doi.org/10.1186/s12882-025-04616-z","journal":{"identity":"bmc-nephrology","isVorOnly":false,"title":"BMC Nephrology"},"publishedOn":"2025-12-23 15:57:32","publishedOnDateReadable":"December 23rd, 2025"},"versionCreatedAt":"2025-08-17 14:17:20","video":"","vorDoi":"10.1186/s12882-025-04616-z","vorDoiUrl":"https://doi.org/10.1186/s12882-025-04616-z","workflowStages":[]},"version":"v1","identity":"rs-7138364","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7138364","identity":"rs-7138364","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}